Most women, at least once in their lifetime, suffer from vaginal fungal infection. There are a variety of reasons for these infections to occur. The widespread use of antibiotics encourages the overgrowth of Candida albicans. This condition, known as vulvovaginitis (vulvovaginal Candidiasis or VVC) is usually treated by azole antifungal agents applied either intravaginally or orally. However, sufferers often mistakenly believe that their vaginal infection is a fungal infection that can be treated with over-the-counter (OTC) antifungal products. Such sufferers may actually have a bacterial infection, rather than a fungal infection. OTC antifungal products are not effective against bacterial infections (also known as “bacterial vaginosis”), a chronic condition which is much more common than VVC. Clinically, bacterial vaginosis is a polymicrobial vaginal infection caused by an increase in the number of anaerobic organisms with a concomitant decrease in Lactobacilli in the vagina. Indiscriminate use of OTC antifungal products may lead to an added risk of masking bacterial infections.
Under stable conditions, Lactobacilli, the predominant organism in the normal vagina, control the growth of anaerobes and other bacteria by producing hydrogen peroxide and lactic acid from vaginal glycogen to maintain vaginal acidity. Therefore, it is of prime importance that products and compositions intended for vaginal application for treatment of fungal or bacterial infections do not adversely affect the Lactobacilli population and that they permit a healthy acidic vaginal pH to be maintained.
Although the incidence of vaginitis and bacterial vaginosis is staggering, there are only a small number of products currently available to treat bacterial infections. For example, MetroGel-Vaginal® (metronidazole) and Cleosin® (clindamycin) are available by prescription to treat bacterial vaginosis. However, it has been found that about 15–30% of patients who contract bacterial vaginosis develop a post-treatment VVC infection.
Thus, there is a pressing need for a product that will treat both VVC and bacterial vaginosis by killing the causative organisms, and thereby treat vaginal infections whether caused by fungus or bacteria.
Known treatments for VVC and bacterial vaginosis generally relate to new antifungal and antibacterial chemical entities and penetration-enhancing formulations that increase the availability of existing compounds.
For example, WO 99/63968A1 relates to increased solubility of poorly-soluble antibacterial and antifungal agents via aqueous preparations and reversibly heat-gelling aqueous preparations using polysorbate and/or polyoxyethylene-hardened castor oil. WO99/43343A1 and U.S. Pat. No. 6,093,391 describe enhanced activity of peptide-based and other treatment agents, including azole antifungals, utilizing Pluronic P85 as a gelling agent. GB 2,327,344 discusses azole antifungal/antibacterial derivatives in formulations in combination with silver slats for treatment of wounds, ulcers and burns. GB 2,187,956 and U.S. Pat. No. 4,803,066 describe a topical pharmaceutical composition using a mixture of an antimicrobial silver compound in combination with an azole compound to treat burns, ulcers, skin and mucous membrane lesions and infections. FR 2,805,745 describes antifungal and antiseptic nail varnish compositions containing a cellulosic film forming agent in solution with an organic solvent and formalin. WO99/18791 describes the use of an amino acid derivative in the free acid or salt form, in which the nitrogen atoms of two or more amino acid molecules are linked by a hydrocarbyl substituted hydrocarbyl group as an antifungal compound and/or an antibacterial compound.
Previous efforts to solubilize azole antifungal products such as miconazole, terconazole, itraconazole, clotrimazole and others have involved the use of organic solvents such as ethyl alcohol in combination with other organic solvents. However, alcohol-based compositions are irritating to mucous membranes and cannot be used in preparations intended for vaginal or oral application.
Therefore, there remains a need for an effective, efficient product that is capable of addressing both VVC and bacterial vaginosis while selectively permitting the survival and maintenance of the vaginal Lactobacillus population.
One objective of this invention is to provide a means for solubilizing insoluble or sparingly-soluble azole compounds in order to increase their efficacy and spectrum of their activity. It is also an object of this invention to develop novel compositions that will be effective to treat both fungal and bacterial infections.